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Carcinogenicity

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Although the available animal and human data on the carcinogenicity of copper and its compounds are deficient in several respects, the findings do not raise concerns with respect to carcinogenic activity.  Consequently, further tests investigating this end-point are not recommended.  
The studies on carcinogenicity also give information on the chronic effects of copper on rats and mice. The studies, although limited, indicate that at the doses tested, the pivotal endpoint was a reduction in weight gain at the highest dose rates tested. These results indicate that the NOAEL values derived from the sub-chronic effects observed in the NTP study, 1993 could be regarded as worst case for the risk assessment of. copper and copper compounds.

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Additional information

Non-human information

Carcinogenicity: oral

All available studies on the carcinogenicity of copper are public domain studies and therefore, taken in isolation are of limited value to ascertain the carcinogenic potential copper compounds. This is due to the fact that these studies are limited due to shorter exposure periods (<2 years) and group sizes being small. However, when the 3 studies summarised below are assessed on an overall balanced approach, the information from these studies does give useful information as to the carcinogenic potential of copper compounds.


Route

Species
Strain
Sex
no/group

dose levels
frequency of application

Tumours

Reference

Oral, diet 9 months

Rat, Sprague-Dawley, male 50 or 58 animals/group

1 ppm, 800 ppm (0.05, 40 mgCu/kg/bw/day)

Liver necrosis and transitional nodules in the liver (3/32) and transitional nodules in the liver (1/32) was observed at 40 mgCu/kg/bw/day whereas one kidney tumour (1/42) was observed in the low copper group (not thought significant). Decreased body weight gain and increased mortality were found in the high copper group. Exposure to known carcinogens increased the incidence of liver necrosis and transitional nodules and each induced a similar incidence of liver tumours in rats fed excess copper or copper-deficient diets. 

In the DMN group, 17/30 rats on the copper-deficient diet and kidney tumours compared to 0/29 given excess copper. The incidence of AAF-induced extrahepatic neoplasms was apparently reduced by the excess copper diet. (5/30 vs 11/27).

Carlton et al, 1973. Dietary copper and the induction of neoplasms in he rat by acetylaminofluorene and dimethylnitrosamine. Fd. Cosmet. Toxicol. Vol 11, 827-840.

Oral drinking water 46 weeks

Mouse C57BL/6J, female 10-12 animals/group

198 mg/l

(app. 10 mgCu/kg/bw/day)

The incidences of ovarian tumours after 46 weeks were 0/10, 0/12, 11/11 and 6/11 in the untreated controls, copper treated mice, DMBA-treated mice and DMBA-copper-treated mice respectively. This suggests that copper sulphate may possibly inhibit DMBA-induced tumour development. CuSO4 had no effect on the incidence of DMBA-induced adenomas of the lung, lymphomas and breast tumours.

Burki & Okita, 1969. Effects of oral copper sulfate on 7, 12 dimethyl

benz(a)anthracene carcinogenesis in mice. Br. J. Cancer Sep. 23(3): 591-596

Oral diet, 30-44 weeks

Rat, Sprague-Dawley, male and female, 23-26 animals/ group

0, 530 or 1600 ppm Cu (approx. 0, 27 or 80 mg Cu/kg b.w./day in males and 0, 40 or 120 mg Cu/kg b.w./day in females).

The growth of rats receiving 1600 ppm Cu as CuSO4 was adversely affected, although organ weights were apparently unaffected (other than increased stomach weight in females). Well-defined abnormalities evident in the 1600 ppm treatment group included ‘bronzed’ kidneys, ‘bronzed’ or yellowish livers, hypertrophied ridges between cardiac and peptic portions of the stomach and blood in the intestinal tract. Histological examination revealed varying degrees of testicular degeneration in rats from both the 530 ppm and the 1600 ppm groups and effects on the liver were seen in both males and females. There were no reports of evidence of neoplasms in any treatment group.

Harrison et al, 1954. The safety and fate of potassium sodium copper chlorophyllin and other copper compounds. Journal of the American Pharmaceutical Association, 43(12): 722-737.

 


All available studies on the carcinogenicity of copper are public domain studies and therefore, taken in isolation are of limited value to ascertain the carcinogenic potential copper compounds and are given a Quality Criteria of 3 individually. This is due to the fact that these studies are limited due to shorter exposure periods (<2 years) and group sizes being small. However, when the 3 available studies are assessed on an overall balanced approach, they give useful information as to the carcinogenic potential of copper compounds.

These results indicate that copper sulphate and other copper salts do not appear to have carcinogenic potential even at very high dose levels of up to 120 mg Cu/kg/bw/day (Harrison et al., 1954). The data in Carlton et al, 1973 are especially useful since positive control groups were added in this study and showed an induction of neoplasms in the rat, indicating that the exposure period (although not two years) was long enough for neoplasms to appear if you have a positive carcinogen. In addition, this study indicates that excess copper may have a protective effect on known carcinogens.

These animal carcinogenicity studies have been conducted with copper compounds. Short duration, small sample sizes and limited histopathologic examination limit the findings of the studies. Nevertheless, the findings of these studies do not raise concerns with respect to carcinogenic activity.

Chronic toxicity investigations in these studies, and in particular, in Harrison et al., 1954, indicate that, as in the pivotal 90-day rat study of Hebert, 1993, the target organs for copper are the liver and kidney. In addition, the longer duration studies indicate that the adverse effects do not appear to become more severe over longer exposure periods (up to one year). This is probably due to the homeostatic control mechanisms present in animals which would regulate the uptake and excretion of copper on a daily basis. As adverse effects are only observed at relatively high levels of copper outside the normal daily intake of copper for humans (up to 10 mg/day), new chronic studies extending over a 2 year time period are not expected to add further insight into the mechanisms of chronic toxicity and carcinogenicity of copper in humans.

In addition, the available genotoxicity studies support the indication that copper compounds have no carcinogenic potential. The studies include Ames assays in Salmonella typhimurium on copper II sulphate pentahydrate; a micronucleus study on copper II sulphate pentahydrate and an unscheduled DNA synthesis ex vivo study in rat liver on copper II sulphate.

The Ames tests indicated that copper sulphate had no mutagenic activity (Ward, 1994). No evidence of an increase in the incidence of micronuclei was detected in the mouse micronucleus study when mice were orally administered two doses of 447 mg/kg copper sulphate, 24 h apart (Riley, 1994). There was also no evidence of unscheduled DNA synthesis in the rat liver (Ballantyre, 1994).

These studies are consistent and show a lack of in vitro mutagenic activity or in vivo clastogenic potential associated with soluble copper compounds. The results of these studies do not highlight a concern regarding the genotoxic potential of copper compounds.

Available data on the genotoxicity and carcinogenicity of copper and its compounds have been considered against EU classification criteria. The available data for copper compounds do not meet the criteria requiring classification for carcinogenicity.

 

Justification for classification or non-classification